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2014 The American Academy of Neurology Institute.

EPILEPSY SYNDROMES AND THEIR TREATMENTS: AN UPDATE

Howard P. Goodkin, MD, PhDUniversity of VirginiaCharlottesville, VA

"The seizure is only the symptom that brings the patient to the physician. The epilepticsyndrome of which the seizure is a symptom is the determinant of the prognosis and is theproduct of the underlying disease. Thus, the family history, age at onset, rate of progression,presence or absence of neurological abnormalities, presence or absence of interictalelectroencephalographic (EEG) abnormalities, and response to medication all contribute to thediagnosis of the syndrome. (Dreifuss and Ogunyemi, 1992)

Modern-day attempts to classify the epilepsies date back to 1969 (Gastaut, 1969), with the International LeagueAgainst Epilepsy (ILAE) publishing its first official proposed classification of the epilepsies in 1970 (Merlis, 1970).Subsequent clarifications or revisions were published in 1985, 1989, 2001, 2006, and, most recently, 2010 (Seesection E. References for ILAE Classifications). The continued need to modify the initial proposal represents anevolution necessitated by advances in genetics, imaging, and basic science (Berg et al, 2010).

The changes proposed in the 2010 report of the ILAE Commission on Classification and Terminology (Berg et al,2010) represent a major transformation from the previous classification schemes. Lost is the prior dichotomy oflocalization-related vs. generalized epilepsy. In the newly proposed system, the epilepsies are subdivided intoelectroclinical syndromes (i.e. clinical entities that are identifiable on the basis of a typical age onset, specificEEG characteristics, seizure type, and often other features which, when taken together, permit a specificdiagnosis; Berg et al, 2010) sorted based on age of onset; constellations (clinically distinctive entities on thebasis of specific lesions or other causes; many of these constellations are amenable to epilepsy surgery);structural/metabolic epilepsies (epilepsies secondary to structural or metabolic lesions or conditions not fittingelectroclinical syndromes); and epilepsies of unknown cause. For an ongoing discussion of the proposed changesand possible revisions, please refer to the following website hosted by the ILAE (last accessed on February 2,2014): http://www.ilae.org/Visitors/Centre/Organization.cfm

A. The Causes of Epilepsy.

The 2010 Commission report recommends that the terms that have been used to separate the epilepsies basedon cause (idiopathic, cryptogenic, and symptomatic) be removed from the epilepsy lexicon as these words werefrequently misused and are no longer relevant given recent advances in genetics. The 2010 report proposed thatetiology should be classified as genetic, structural-metabolic, and unknown cause. More recently, it has beenrecommended that the etiological categories been expanded to six non-exclusive etiological causes: genetic,structural, metabolic, immune, infectious, and unknown(www.ilae.org/Visitors/Centre/Documents/OrganizationEpilepsy.pdf).

Of the prior terms, idiopathiccreated the most confusion over the years. Prior to the 19thcentury, the term

idiopathicdescribed any epilepsy of cerebral origin in contrast to those epilepsies which may arise from anotherpart of the body (e.g. stomache). The intended purpose of this term within the ILAE classification system was todifferentiate the idiopathicor primary epilepsies from the symptomaticor secondary epilepsies. The idiopathicepilepsies were those that occurred in the absence of a structural lesion or cognitive/psychiatric comorbidities,were frequently self-limited, and of presumed genetic etiology (Committee on Classification and Terminology of

the ILAE, 1989). Based on these features, the implication was that an idiopathicepilepsy was benign, in contrastto the symptomatic epilepsies that tend to persist, be resistant to medication, and often had obviouscognitive/psychiatric comorbidities (Dreifuss and Henriksen, 1992; see Section B. Old Labels for furtherdiscussion of the term benign).

However, these prior concepts no longer hold. First, the idiopathic epilepsies are not necessarily void of cognitiveand behavioral dysfunction (e.g. Wirrell et al, 1997; Wirrell, 2003;Trinka et al, 2006; Moschetta et al, 2011).Second, there are increasing examples in which a genetic etiology can be associated with difficult-to-treat


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epilepsy and a poor developmental outcome. (Note: Although genetic and inherited are not synonymous,replacement of idiopathicwith genetichas been criticized due to the potential negative psychological and socialimpact that being diagnosed with a genetic epilepsymay have on the patient or their family).

An example of a recently described genetic epilepsy associated with moderate-to-profound intellectual disability isKCNQ2encephalopathy (Weckhuysen et al, 2012; Saitsu et al, 2012; Kato et al, 2013; Milh et al, 2013;Weckhuysen et al, 2013) that results from mutations of KCNQ2, which encodes for potassium voltage-gatedchannel, KQT-like subfamily, member 2. This protein is a subunit of the M channel, a slowly activating and

deactivating potassium channel involved in regulation of neuronal excitability.

Mutations of KCNQ2 were first linked to benign familial neonatal seizures (BFNS; Biervert et al, 1998; Singh et al,1998). This familial electroclinical syndrome (Wirrell and Nickels, 2010) consists of focal, multifocal, as well asgeneralized seizures in an otherwise healthy full term newborn. Frequently, these events are described as brief(seconds to minutes) episodes of tonic posturing of the limbs that can be associated with a shrill cry and apnea.Untreated the seizure can occur frequently throughout the day and status epilepticus has been observed. Theinterictal EEG is often normal; although focal epileptiform discharges may be present. Electrographically, the ictalevent is associated with generalized suppression. Imaging should be normal.

Typically age of onset BFNS is the first week of life (day 2 to 8); however, onset can occur as late as 4 months.The epilepsy is self-limited with most children seizure free by 18 months and developmental outcome is good.However, upwards of 15% may develop epilepsy later in life with generalized tonic or tonic-clonic seizures.

Given reports of unfavorable outcome associated with KCNQ2 mutations and BFNS (Dedek et al, 2003; Borgattiet al, 2004; Steinlein et al, 2007; Schmitt et al, 2005), Weckhuysen and colleagues (2012) screened a cohort of80 children with intellectual disability in the setting of neonatal or early infantile onset (


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typically alerted to the seizure by a guttural sound prior to rapid secondary generalization. The majority ofseizures are short; however, status epilepticus has been reported. The pathognomic interictal EEG demonstratesthe presence of a centrotemporal dipole. Imaging of the head is typically normal.

The peak age of onset of BECTS is approximately 6-7 years of age, with the majority of cases presentingbetween 5 and 10 years of age. However, rare cases as young as 1 year and as old as 16 years have beenreported. Some choose not to treat BECTs as it is unusual for these children to have more than 3 seizures andthere is often spontaneous remission within 2 to 4 years of presentation. Antiseizure medications that have been

used to treat this condition include carbamazepine, valproate, gabapentin, levetiracetam, and oxcarbazepine(Glauser et al, 2013)

In the report that proposed the benign designation for this syndrome, Blom and colleagues (1972) reported on thelong term outcome of 23 patients older than 18 years of age. It is stated that none of them had experienced anydifficulty in school or choosing a profession because of their seizures. Although more modern studies havedemonstrated good long term cognitive outcome (e.g. Lindgren et al, 2004; Callenbach et al 2010), there isincreasing evidence for cognitive and learning difficulties during the years that the epilepsy is active (e.g.Northcott et al, 2007; Kramer, 2008; Genizi et al, 2012; Besseling et al, 2013).

As alternative to benign(and idiopathic when the intent was to imply a favorable outcome), the Committee hasproffered self-limitedand pharmacoresponsive. The attempt to limit the use of benignis not without its critics (e.g.Panayiotopoulos, 2012). However, despite the Committees recommendation, it is suspected that many will

continue to designate these syndromes as benign, especially as the syndromic names in this category have notyet been changed.

CATASTROPHIC. The 2010 Committee report also recommends that the term catastrophicbe shed due to itsstrong emotional overtones. For the epilepsies previously designated catastrophic, the 2010 Committee reportendorses the concept of epileptic encephalopathy, which was originally introduced in 2006.

The distinctive feature of an epileptic encephalopathy is the presence of severe cognitive and behavioralimpairments that commence and/or worsen after the onset of the epilepsy. For these syndromes, it is proposedthat that the epileptic activity may contribute to the encephalopathy. The electroclinical syndromes that fall underthis rubric include Ohtahara syndrome, Early Myoclonic Encephalopathy, West Syndrome, Dravet Syndrome,Lennox-Gastaut syndrome, and Landau-Klefner syndrome. As a group, these disorders tend to be difficult to treat(i.e. pharmacoresistant).

A prototypic epileptic encephalopathy is West syndrome (Tuxhorn, 2011). West syndrome is characterized by thetriad of epileptic spasms, an interictal EEG demonstrating the presence of hypsarrhythmia, and a severeintellectual disability. The spasms consist of brief, massive flexion, extension, or mixed contraction of the axialmusculature typically shortly after awakening, tending to occur in clusters, and coincident with anelectrodecrement on the EEG. The majority of children present between 3 and 7 months of age. The causes ofWest Syndrome are multiple and include neurocutaneous syndromes, brain malformations and tumors, acquiredinjuries, inborn errors of metabolism, and an expanding list of genetic mutations (e.g. ARX, CDKL5, FOXG1).

Standard initial treatment for West Syndrome includes hormonal therapies (ACTH or prednisolone) or vigabatrin.Options for refractory epileptic spasms have included the ketogenic diet, valproate, and potentially surgery whena focal lesion is identified. The recent evidenced-based guideline from the American Academy of Neurology andthe Practice Committee of the Child Neurology Society (Go et al, 2012) recommended hormonal therapy inpreference to vigabatrin for children with infantile spasms of undetermined etiology. Although a low dose ACTH

protocol was recommended, a recent survey of Child Neurology Society members (Mytinger and Joshi, 2012)found that the majority of respondents (n=222; 18.5% of those polled) continue to use high dose ACTH protocolsof 150 IU/m

2/day.

An important question with respect to any epileptic encephalopathy is whether early treatment can affect outcome(Riikonen, 2010). OCallaghan and colleagues (2011) evaluated developmental outcome at 4 years of age of acohort of 77 children previously medically treated for infantile spasms as part of the United Kingdom InfantileSpasms Study (UKISS; Lux et al, 2004). They found that children who were promptly diagnosed and receivedprompt treatment had a better developmental outcome. Similarly, Mathern and colleagues (Jonas et al, 2005)demonstrated that early surgical intervention for children with medically refractory infantile spasms was


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associated with a better developmental outcome. These findings provide support to the hypothesis that earlyidentification and treatment of an epileptic encephalopathy can alter the developmental trajectory of thesechildren.

C. NEW SYNDROMESThree new syndromes are included in the 2010 Committee report: genetic epilepsy with febrile seizures plus(GEFS+), autosomal dominant frontal lobe epilepsy (ADNFLE), and autosomal dominant lateral temporal lobeepilepsy (ADLTE; a.k.a. autosomal dominant partial epilepsy with auditory features, ADPEAF).

GEFS+ (Scheffer et al, 2009) is a heterogeneous electroclinical syndrome characterized by the presence of bothfebrile seizures, which persist beyond 6 years of age, and afebrile seizures (generalized tonic-clonic, myoclonic,absence, astatic, and focal-onset seizures). The interictal EEG may be normal or demonstrate nonspecificfindings that include typical 3 Hz generalized spike waves and focal discharges. Imaging is typically normal.Treatment is determined by seizure type with the majority of children with this syndrome remitting byadolescence.

The diagnosis of GEFS+ is dependent on a family history of epilepsy that can range from simple febrile seizuresto Dravet syndrome. Inheritance occurs in an autosomal dominant pattern with penetrance ranging from 60-90%.The initial family described by Scheffer and Berkovich (1997) were later found to have a mutation in the voltage-gated sodium channel 1 subunit gene (SCN1B). In the interim, mutations of SCN1A, SCN2A, SCN9A ,GABARG2, and GABRDhave all been correlated with a GEFS+ phenotype.

ADNFLE (Steinlein, 2001) is characterized by focal seizures of frontal lobe onset consisting of brief dystonicposturing followed by complex hypermotor activity and moaning. An aura of fear may also be described. Clustersof brief (5 to 30 seconds) seizures may occur during non-REM sleep. Daytime seizures are rare. Seizure onset istypically around 11-12 years of age with a range of 1 to 30 years. ADNFLE is often initially misdiagnosed asnightmares or other parasomnias. Abnormalities that have been observed on interictal EEG include focal slowingor attenuation over the anterior head regions and frontally dominant paroxysmal epileptiform discharges. Ictally,bifrontal, high-voltage sharp and slow waves or low-amplitude, paroxysmal fast activity may be observed. Headimaging is normal. Cognitive comorbidities are rare but can occur. The seizures typically respond well totreatment and reduce in frequency as the patient ages.

A family history of nocturnal frontal lobe epilepsy may be present or affected family members may have beenpreviously misdiagnosed with a parasomnia or behavioral problem. Inheritance is autosomal dominant withincomplete penetrance (~30 to 100%). ADNFLE has been linked to mutations of genes encoding the 2(CHRNA2), 4 (CHRNA4), and 2 (CHRNB2) subunits of the nicotinic acetylcholine receptors (nACHR).Mutations of KCNT1, which encodes the sodium-activated potassium channel subunit KCNT1 (a.k.a, KCa4.1),have been found in families and a sporadic case in which there were comorbid psychiatric features thataccompanied the nocturnal frontal lobe seizures (Heron et al, 2012).

ADLTE/ADPEAF (Nobile et al, 2009) is characterized by focal seizures that arise from the cortex of the lateraltemporal lobe and frequently have a prominent auditory aura that manifests as ringing, whistling, orhumming/singing. Associated features have included reports of ictal aphasia as well as other sensory symptomssuch as complex visual hallucinations, psychic auras, olfactory hallucinations and vertigo. Secondarygeneralization can occur. These seizures can be triggered by sounds. Seizure onset is typically duringadolescence but can be variable (typically 18 years of age, range 1 year to 60 years). Diagnosis may be delayedas the symptoms can be mild. Interictal EEG findings may demonstrate focal temporal slowing. MRI of the brain isusually normal. The seizures are responsive to standard antiseizure medications but may recur when the drug is

discontinued.

ADLTE is inherited in an autosomal dominant pattern with penetrance rates ranging from approximately 50 to85%. In several families with ADLTE, this syndrome was associated with a mutation of the LGI1 (leucine-rich,glioma-inactivated 1) gene. Unlike other electroclinical syndromes for which a gene mutations have beenidentified, ADLTE is unique in that LGI1 does not encode for an ion channel or receptor subunit. LGI1 isexpressed during neural development and associated with both presynaptic potassium channels and thepostsynaptic protein complex. Yet, how this mutation triggers epileptogenesis remains unknown.


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D. PUTTING CLASSIFICATION OF EPILEPSY SYNDROMES TO THE TESTClassification schemes provide for data simplification and a universal language. In terms of epilepsy, theclassification system must be accurate if it is to be used for providing prognostic information and assisting inantiseizure medication choice (Glauser et al, 2013) while also creating a framework upon which clinical trials andother epilepsy research can be performed.

As demonstrated by Berg and colleagues (Berg et al, 1999; Berg et al, 2000), the 1989 classification system hada high degree of accuracy for the syndromic diagnosis of new onset epilepsy in children. In their study, Berg et al.

were able to classify the majority of a prospectively attained cohort of 613 children with new onset epilepsy usingthe 1989 classification system (Berg et al, 1999). Two years later, the cohort was re-examined (Berg et al, 2000).In the majority of cases (~86%), the initial syndromic diagnosis was correct. For those children who requiredreclassification, an expected syndromic evolution (e.g. evolution of West syndrome to Lennox-Gastaut syndrome)occurred in 24 children (~4%). Only approximately 10% (n=60; 9.8%) required rectification of the initial syndromediagnosis. For many of these, classification to a more specific syndrome occurred, often as the result of findingson EEG.

Although no similar study is available for the 2010 revision, van Campen and colleagues (2013) found highinterobserver agreement between the 1989 classification and the 2010 revision suggesting that results similar tothose of Berg and colleagues could be expected using the 2010 revised syndrome format.

D. SUMMARY

The individual epileptic seizure is, as it were, but one of the pigments with which the illness ispainted, the picture of the illness itself is made up of a large number of such individual pigmentsand an arrangement that is specific for the condition under consideration. (Dreifuss andOgunyemi 1992)

It is important to recognize that no classification system is perfect. As we make advances in our understanding ofeach individual pigment within the arrangement that is the epilepsy syndrome, revisions will be required. Ascorrect classification is necessary for guiding decisions regarding the evaluation and management of theepilepsies, it is imperative that the informed physician be aware of evolution within the internationally proposedepilepsy classification system, the rationale for the changes, and the imperfections that still exist.

E. REFERENCES FOR THE ILAE CLASSIFICATIONS OF EPILEPSY1970: Merlis JK. Proposal for an international classification of the epilepsies. Epilepsia 1970;11:114-119.

1985: Commission on Classification and Terminology of the International League against Epilepsy. Proposal forclassification of epilepsies and epileptic syndromes. Epilepsia, 1985;26:268-278.

1989: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal forrevised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-399.

2001: Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of theILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803.

2006: Engel J. Report of the IALE Classification Core Group. Epilepsia 2006;47:1558-1568.

2010: Berg At, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and

epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 5:676-685.

F. NOTEFor a clear and precise description the pediatric epilepsy syndromes and their treatment, the following referenceis recommended:

Wirrell E and Nickels KC. Pediatric Epilepsy Syndromes. Continuum. 2010;16:57-85.


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TABLE. Electroc l inical syn drom es and other epi lepsies (mod if ied from Berg et al, 2010)

Electroclinical syndromesElectroclinical syndrome commencing during the neonatal period:

Benign familial neonatal epilepsy, early myoclonic encephalopathy, Ohtahara syndrome

Electroclinical syndromes commencing during infancy:Epilepsy of infancy with migrating focal seizures, West Syndrome, Myoclonic epilepsy in infancy, Benign

infantile epilepsy, Benign familial infantile epilepsy, Dravet syndrome, Myoclonic encephalopathy innonprogressive disorders

Electroclinical syndromes commencing during childhood:Febrile seizures plus (can start in infancy), Panyiotopoulos syndrome, Epilepsy with myoclonic atonicseizures, Benign epilepsy with centrotemporal spikes, Autosomal-dominant frontal lobe epilepsy, Lateonset childhood occipital epilepsy (Gastaut type), Epilepsy with myoclonic absences, Lennox-Gastautsyndrome, Epileptic encephalopathy with continuous spike-and-wave during sleep, Landau-Klefnersyndrome, Childhood absence epilepsy

Electroclinical syndromes commencing during adolescence or older:Juvenile absence epilepsy, Juvenile myoclonic epilepsy, Epilepsy with generalized tonic-clonic seizuresalone, Progressive myoclonus epilepsies, Autosomal dominant epilepsy with auditory features, Other

familial temporal lobe epilepsies

Electroclinical syndromes with less specific age relationship:Familial focal epilepsy with variable foci (childhood to adult), Reflex epilepsies

Distinctive ConstellationsMesial temporal lobe epilepsy with hippocampal sclerosis, Rasmussen syndrome, Gelastic seizures withhypothalamic hamartoma, Hemiconvulsion-hemiplegia-epilepsy, Other

Structural metabolicMalformations of cortical development, Neurocutaneous syndromes, Tumor, Infection, Trauma, Angioma,Perinatal insults, Stroke, etc

Epilepsies of unknown cause

Conditions with seizures not traditionally considered epilepsyBenign neonatal seizures, Febrile seizures.


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